The present invention relates to new taxoids of general formula: 
their preparation and pharmaceutical compositions containing them.
In general formula (I),
Ar represents an aryl radical,
R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical,
R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents:
a straight or branched alkyl radical containing 1 to 8 carbon atoms; an alkenyl radical containing 2 to 8 carbon atoms; an alkynyl radical containing 3 to 8 carbon atoms; a cycloalkyl radical containing 3 to 6 carbon atoms; a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms; these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals; alkyloxy radicals containing 1 to 4 carbon atoms; dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms; piperidino radicals; morpholino radical; 1-piperazinyl radicals (optionally substituted at position 4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl portion contains 1 to 4 carbon atoms); cycloalkyl radicals containing 3 to 6 carbon atoms; cycloalkenyl radicals containing 4 to 6 carbon atoms; phenyl radicals; cyano radicals; carboxy radicals or alkyloxycarbonyl radicals whose alkyl portion contains 1 to 4 carbon atoms,
or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkyloxy radicals containing 1 to 4 carbon atoms,
or a saturated or unsaturated 4- to 6-membered nitrogen-containing heterocyclyl radical optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.
Preferably, Ar represents a phenyl or xcex1- or xcex2-naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, or iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals;
it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms;
that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms; and
that the aryl radicals are phenyl or xcex1- or xcex2-naphthyl radicals or alternatively Ar represents a 5-membered aromatic heterocyclic radical containing one or more hetero atoms, which are identical or different, chosen from nitrogen, oxygen or sulphur atoms;
Ar optionally being substituted by one or more substituents, which are identical or different, chosen from halogen atoms (fluorine, chlorine, bromine or iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, aryloxy radicals containing 6 to 10 carbon atoms, amino radicals, alkylamino radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, acylamino radicals in which the acyl portion contains 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbon atoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion contains 6 to 10 carbon atoms, cyano radicals, carboxy radicals, carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains 1 to 4 carbon atoms or alkoxycarbonyl radicals in which the alkoxy portion contains 1 to 4 carbon atoms.
More particularly, Ar represents a phenyl, 2- or 3-thienyl or 2- or 3-furyl radical optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms, and alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals.
Still more particularly, Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom or by an alkyl (methyl), alkoxy (methoxy), dialkylamino (diethylamino), acylamino (acetylamino) or alkoxycarbonylamino (tert-butoxycarbonylamino) or 2- or 3-thienyl or 2- or 3-furyl radical.
Regarding the alkoxyacetyl radical for R, the alkoxy portion thereof preferably contains 1 to 8 carbon atoms and, more preferably, 1 to 4 carbon atoms. The alkoxy portion may be linear or branched. Preferred alkoxyacetyl groups include saturated groups such as methoxyacetyl (CH3OCH2C(O)xe2x80x94), ethoxyacetyl (CH3CH2OCH2C(O)xe2x80x94), isopropoxyacetyl ((CH3)2CHOCH2C(O)xe2x80x94), and butoxyacetyl (CH3CH2CH2CH2OCH2C(O)xe2x80x94).
Of even more special interest are the products of general formula (I) in which Ar represents a phenyl or 3-thienyl radical and R1 represents a benzoyl or tert-butoxycarbonyl radical.
According to the present invention, the new taxoids of general formula (I) can be obtained from a product of general formula: 
in which Ar and R1 are defined as above, and
R3 and R4, which are identical or different represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or
alternatively R3 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R4 represents a hydrogen atom, or
alternatively R3 and R4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, and G1 represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical or a hydroxy-protecting group, the procedure being carried out, according to the meanings of R3 and R4, in the following manner:
1) when R3 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or an optionally substituted aryl radical and R4 represents a hydrogen atom, the product of general formula (II) is treated in acidic medium in order to obtain a product of general formula: 
in which Ar, R1 and G1 are defined as above, whose G1 radical is, if necessary, replaced by a hydrogen atom or an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound of formula (III) wherein G1 represents a hydrogen atom.
Regarding the alkoxyacetyl radical for G1, the alkoxy portion thereof preferably contains 1 to 8 carbon atoms and, more preferably, 1 to 4 carbon atoms. The alkoxy portion may be linear or branched. Preferred alkoxyacetyl groups include saturated groups such as methoxyacetyl (CH3OCH2C(O)xe2x80x94), ethoxyacetyl (CH3CH2OCH2C(O)xe2x80x94), isopropoxyacetyl ((CH3)2CHOCH2C(O)xe2x80x94), and butoxyacetyl (CH3CH2CH2CH2OCH2C (O)xe2x80x94).
The deprotection of the side chain of the product of general formula (II) can also be carried out in the presence of an inorganic acid (hydrochloric acid or sulphuric acid) or an organic acid (acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid or p-toluenesulphonic acid), used alone or in the form of a mixture, the procedure being carried out in an organic solvent chosen from alcohols (methanol, ethanol or isopropanol), ethers (tetrahydrofuran, diisopropyl ether or methyl t-butyl ether), esters (ethyl acetate, isopropyl acetate or n-butyl acetate), aliphatic hydrocarbons (pentane, hexane or heptane), halogenated aliphatic hydrocarbons (dichloromethane or 1,2-dichloroethane), aromatic hydrocarbons (benzene, toluene or xylenes) and nitriles (acetonitrile) at a temperature ranging from xe2x88x9210 to 60xc2x0 C., preferably from 15 to 30xc2x0 C. The acid may be used in a catalytic or stoichiometric quantity or in excess.
The deprotection can also be carried out under oxidizing conditions, using for example ammonium cerium(IV) nitrate in an acetonitrile-water mixture or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in water.
The deprotection can also be carried out under reducing conditions, for example by hydrogenolysis in the presence of a catalyst.
When G1 represents a protecting group, it is preferably a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy) carbonyl radical whose replacement by a hydrogen atom is carried out using zinc, optionally combined with copper, in the presence of acetic acid, at a temperature ranging from 20 to 60xc2x0 C. or by means of an inorganic or organic acid such as hydrochloric acid or acetic acid in a solution in an aliphatic alcohol containing 1 to 3 carbon atoms or in an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, or alternatively, when G1 represents an alkoxyacetyl radical, its optional replacement by a hydrogen atom is carried out by treatment in alkaline medium or by the action of a zinc halide under conditions which do not affect the rest of the molecule. Generally, the alkaline treatment is carried out by the action of ammonia in aqueous-alcoholic medium, at a temperature close to 20xc2x0 C. Generally, the treatment with a zinc halide, preferably zinc iodide, is carried out in methanol at a temperature close to 20xc2x0 C.
2) when R3 and R4, which are identical or different, represent an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms and the aryl portion is preferably an optionally substituted phenyl radical, or alternatively R3 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R4 represents a hydrogen atom, or alternatively R3 and R4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, the product of general formula (II) is converted to the product of general formula: 
in which Ar and G1 are defined as above, which is acylated by means of benzoyl chloride or a reactive derivative of general formula:
R2xe2x80x94Oxe2x80x94COxe2x80x94Xxe2x80x83xe2x80x83(V)
in which R2 is defined as above and X represents a halogen atom (fluorine or chlorine) or a residue xe2x80x94Oxe2x80x94R2 or xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94R2, to give a product of general formula (III) in which Ar, R1 and G1 are defined as above, whose G1 radical is, if necessary, replaced by a hydrogen atom and then by an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or a derivative therof on a compound represented by the formula (I) wherein R represents a hydrogen atom.
The products of general formula (IV) can be obtained by treating a product of general formula (II), in which Ar, R1 and G1 are defined as above, R3 and R4, which are identical or different, represent an alkyl, aralkyl or aryl radical, or alternatively R3 and R4 form together with the carbon atom to which they are attached a 4- to 7-membered ring, with an inorganic acid (preferably hydrochloric acid or sulphuric acid) or an organic acid (preferably formic acid) optionally in an alcohol containing 1 to 3 carbon atoms (preferably methanol, ethanol or isopropanol) at a temperature ranging from 0 to 50xc2x0 C. Preferably, formic acid is used at a temperature close to 20xc2x0 C.
The acylation of the product of general formula (IV) by means of benzoyl chloride or a reactive derivative of general formula (V) is carried out in an inert organic solvent chosen from esters such as ethyl acetate, isopropyl acetate or n-butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. The reaction is carried out at a temperature ranging from 0 to 50xc2x0 C., preferably close to 20xc2x0 C.
When the radical G1 represents a protecting group, its replacement by a hydrogen atom is carried out under the conditions described above.
The products of general formula (II) can be obtained according to one of the following methods:
1) by esterification of the product of general formula: 
in which G1 is defined as above, by means of an acid of general formula: 
in which Ar, R1, R3 and R4 are defined as above, or of a derivative of this acid.
The esterification by means of an acid of general formula (VII) can be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridine) in an organic solvent (ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at a temperature ranging from xe2x88x9210 to 90xc2x0 C.
The esterification may also be performed using the acid of general formula (VII) in anhydride form, the procedure being carried out in the presence of an activating agent (aminopyridine) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at a temperature ranging from 0 to 90xc2x0 C.
The esterification can also be performed using the acid of general formula (VII) in halide form or in anhydride form with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base (tertiary aliphatic amine), the procedure being carried out in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at a temperature ranging from 0 to 80xc2x0 C.
The acid of general formula (VII) can be obtained by saponification of an ester of general formula: 
in which Ar, R1, R3 and R4 are defined as above and R5 represents an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl radical.
Generally, the saponification is carried out by means of an inorganic base (alkali metal hydroxide, carbonate or bicarbonate) in aqueous-alcoholic medium (methanol-water) at a temperature ranging from 10 to 40xc2x0 C.
The ester of general formula (VIII) can be obtained by the action of a product of general formula: 
in which R3 and R4 are defined as above in the form of a dialkylacetal or an enol alkyl ether, on an ester of general formula: 
in which Ar, R1 and R5 are defined as above, the procedure being carried out in an inert organic solvent (aromatic hydrocarbon) in the presence of a strong inorganic acid (sulphuric acid) or organic acid (p-toluenesulphonic acid optionally in the form of a pyridinium salt) at a temperature ranging from 0xc2x0 C. to the boiling temperature of the reaction mixture.
The ester of general formula (X) can be obtained by the action of a product of general formula (V) on an ester of general formula: 
in which Ar and R5 are defined as above, the procedure being carried out in an organic solvent (ester, halogenated aliphatic hydrocarbon) in the presence of an inorganic or organic base at a temperature ranging from 0 to 50xc2x0 C.
The product of general formula (XI) can be obtained by reduction of an azide of general formula: 
in which Ar and R5 are defined above, by means of hydrogen in the presence of a catalyst such as palladium on carbon, the procedure being carried out in an organic solvent (ester).
The product of general formula (XII) can be obtained by the action of an azide such as trimethylsilyl azide in the presence of zinc chloride or alkali metal (sodium, potassium or lithium) azide in aqueous-organic medium (water-tetrahydrofuran) at a temperature ranging from 20xc2x0 C. to the boiling temperature of the reaction mixture, on an epoxide of general formula: 
in which Ar and R5 are defined as above, optionally prepared in situ.
The epoxide of general formula (XIII) can be obtained, optionally in situ, by dehydrohalogenation of a product of general formula: 
in which Ar is defined as above, Hal represents a halogen atom, preferably a bromine atom, and R6 and R7, which are identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical, at least one being an alkyl radical or a phenyl radical, by means of a alkali-metal alcoholate, optionally prepared in situ, in an inert organic solvent such as tetrahydrofuran at a temperature ranging from xe2x88x9280xc2x0 C. to 25xc2x0 C.
The product of general formula (XIV) can be obtained by the action of an aldehyde of general formula:
Arxe2x80x94CHOxe2x80x83xe2x80x83(XV)
in which Ar is defined as above, on a halide of general formula: 
in which Hal, R6 and R7 are defined as above, anionized beforehand.
Generally, the procedure is carried out in an inert organic solvent chosen from ethers (ethyl ether) and halogenated aliphatic hydrocarbons (methylene chloride) at a temperature ranging from xe2x88x9280 to 25xc2x0 C., in the presence of a tertiary amine (triethylamine) and an enolysing agent (di-n-butylboron triflate).
The product of general formula (XVI) can be obtained by the action of a halide of a haloacetic acid, preferably bromoacetic acid bromide, on the corresponding oxazolidinone.
The product of general formula (XI) can be obtained by hydrogenolysis of a product of general formula: 
in which Ar and R5 are defined as above and Ph represents an optionally substituted phenyl radical.
Generally, the hydrogenolysis is carried out by means of hydrogen in the presence of a catalyst. More particularly, palladium on carbon containing 1 to 10% by weight of palladium or palladium dihydroxide containing 20% by weight of palladium is used as catalyst.
The hydrogenolysis is carried out in an organic solvent or in a mixture of organic solvents. It is advantageous to carry out the procedure in acetic acid optionally combined with an aliphatic alcohol containing 1 to 4 carbon atoms such as a mixture of acetic acid-methanol at a temperature ranging from 20 to 80xc2x0 C.
The hydrogen necessary for the hydrogenolysis can also be provided by a compound which liberates hydrogen by chemical reaction or by thermal decomposition (ammonium formate). It is advantageous to carry out the procedure at a hydrogen pressure ranging from 1 to 50 bar.
The product of general formula (XVII) can be obtained by hydrolysis or alcoholysis of a product of general formula: 
in which Ar and Ph are defined as above.
It is particularly advantageous to carry out an alcoholysis by means of an alcohol of formula R5xe2x80x94OH in which R5 is defined as above, the procedure being carried out in acidic medium.
Preferably, the alcoholysis is carried out by means of methanol in the presence of a strong inorganic acid such as hydrochloric acid at a temperature close to the reflux temperature of the reaction mixture.
The product of general formula (XVIII) can be obtained by saponification of an ester of general formula: 
in which Ar and Ph are defined as above and R8 represents an alkyl, phenylalkyl or phenyl radical, followed by separation of the 3R, 4S diastereoisomer of general formula (XVII) from the other diastereoisomers.
Generally, the saponification is carried out by means of an inorganic or organic base such as ammonium hydroxide, lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as a methanol-water or tetrahydrofuran-water mixture at a temperature ranging from xe2x88x9210xc2x0 C. to 20xc2x0 C.
The separation of the 3R, 4S diastereoisomer can be carried out by selective crystallization from a suitable organic solvent such as ethyl acetate.
The product of general formula (XIX) can be obtained by cycloaddition of an imine of general formula: 
in which Ar and Ph are defined as above, onto an acid halide of general formula: 
in which R8 is defined as above and Y represents a halogen atom such as a bromine or chlorine atom.
Generally, the reaction is carried out at a temperature ranging from 0 to 50xc2x0 C. in the presence of a base chosen from aliphatic tertiary amines (triethylamine) or pyridine in an organic solvent chosen from optionally halogenated aliphatic hydrocarbons (methylene chloride or chloroform) and aromatic hydrocarbons (benzene, toluene or xylenes).
The product of general formula (XX) can be obtained under conditions analogous to those described by M. Furukawa et al., Chem. Phar. Bull., 25 (1), 181-184 (1977).
The product of general formula (VI) can be obtained by the action of an alkali metal halide (sodium iodide or potassium fluoride) or an alkali metal azide (sodium azide) or a quaternary ammonium salt or an alkali metal phosphate, on a baccatin III or 10-deacetylbaccatin III derivative of general formula: 
in which G1 is defined as above.
Generally, the reaction is carried out in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl t-butyl ether) and nitriles (acetonitrile), alone or in the form of a mixture, at a temperature ranging from 20xc2x0 C. to the boiling temperature of the reaction mixture.
The product of formula (XXII) in which G1 represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical can be obtained by the action of a trifluoromethanesulphonic acid derivative such as the anhydride or N-phenyltrifluoromethanesulphonimide, on baccatin III or 10-deacetylbaccatin III, which can be extracted according to known methods from yew leaves (Taxus baccata), optionally followed by protection in position 10, it being understood that in order to obtain a product of general formula (XXII) in which G1 represents an alkoxyacetyl or alkyl radical, it is necessary to treat beforehand the 10-deacetylbaccatin III protected in position 7, preferably with a silylated radical, with an alkoxy acetic acid halide or with an alkyl halide.
Generally, the reaction of a trifluoromethanesulphonic acid derivative is carried out in an inert organic solvent (optionally halogenated aliphatic hydrocarbons, or aromatic hydrocarbons) in the presence of an organic base such as an aliphatic tertiary amine (triethylamine) or pyridine, at a temperature ranging from xe2x88x9250 to +20xc2x0 C.
Generally, the introduction of an alkoxyacetyl group is carried out by treating the protected 10-deacetylbaccatin III with an alkoxyacetic acid halide, the procedure being carried out in a basic organic solvent such as pyridine at a temperature close to 20xc2x0 C.
Generally, the introduction of an alkyl radical is carried out by treating the 10-deacetylbaccatin III, protected and metallized in position 10, by means, for example, of a alkali metal hydride (sodium hydride) or a metallic alkylide (butyllithium), with an alkyl halide.
2) by the action of an alkali metal halide (sodium iodide or potassium fluoride) or an alkali metal azide (sodium azide) or a quaternary ammonium salt or an alkali metal phosphate on a product of general formula: 
in which Ar, R1, R3, R4 and G1 are defined as above.
Generally, the reaction is carried out in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether or methyl t-butyl ether) and nitriles (acetonitrile), alone or in the form of a mixture, at a temperature ranging from 20xc2x0 C. to the boiling temperature of the reaction mixture.
The product of general formula (XXIII) can be obtained by the action of a trifluoromethanesulphonic acid derivative such as the anhydride or N-phenyltrifluoromethanesulphonimide on a taxoid of general formula: 
in which Ar, R1, R3, R4 and G1 are defined as above.
Generally, the reaction is carried out in an inert organic solvent (optionally halogenated aliphatic hydrocarbons, or aromatic hydrocarbons) in the presence of an organic base such as an aliphatic tertiary amine (triethylamine) or pyridine, at a temperature ranging from xe2x88x9250 to +20xc2x0 C.
The taxoid of general formula (XXIV), in which G1 represents a hydrogen atom or an alkoxyacetyl radical, can be obtained from a product of general formula: 
in which Ar, R1, R3, R4 are defined as above, Gxe2x80x21 represents a hydroxy-protecting group and Gxe2x80x22 represents an alkoxyacetyl radical or a hydroxy-protecting group, by replacement of the protecting group Gxe2x80x21 by a hydrogen atom and optionally Gxe2x80x22 by a hydrogen atom and then by an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or a derivative thereof on a compound represented by the formula (I) wherein R represents a hydrogen atom.
The radicals Gxe2x80x21 and Gxe2x80x22 when they represent a hydroxy-protecting group are preferably 2,2,2-trichloroethoxycarbonyl or 2-(trichloromethyl-propoxy)carbonyl radicals or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which the alkyl portions contain 1 to 4 carbon atoms and the aryl portions are preferably phenyl radicals, it being possible, in addition, for Gxe2x80x22 to represent an alkoxyacetyl radical.
When Gxe2x80x21 and Gxe2x80x22 represent a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, the replacement of the protecting groups by hydrogen atoms is carried out using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 20 to 60xc2x0 C. or by means of an inorganic or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper.
When Gxe2x80x21 represents a silylated radical and Gxe2x80x22 represents an alkoxyacetyl radical, the replacement of the protecting group Gxe2x80x21 by a hydrogen atom can be carried out by means of, for example, gaseous hydrochloric acid in ethanolic solution at a temperature close to 0xc2x0 C., under conditions which are without effect on the rest of the molecule.
When Gxe2x80x22 represents an alkoxyacetyl radical, its optional replacement by a hydrogen atom is carried out by treatment in alkaline medium or by the action of a zinc halide under conditions which do not affect the rest of the molecule. Generally, the alkaline treatment is carried out by the action of ammonia in aqueous-alcoholic medium, at a temperature close to 20xc2x0 C. Generally, the treatment with a zinc halide, preferably zinc iodide, is carried out in methanol at a temperature close to 20xc2x0 C.,
The product of general formula (XXV) can be obtained under the conditions described in international application PCT/WO 9209589, the disclosure of which is incorporated by reference herein.
The new derivatives of general formula (I) can also be obtained by esterification of a product of general formula (VI) by means of an acid of general formula: 
in which Ar and R1 are defined as above and G3 represents a hydroxy-protecting group chosen from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (xcex2-trimethylsilyloxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl, 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radicals or CH2xe2x80x94Ph radicals in which Ph represents a phenyl radical optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms, or an activated derivative of this acid, to give a product of general formula: 
in which Ar, R1, G1, and G3 are defined as above, followed by the replacement of the protecting group G3 by hydrogen atom and optionally G1 by a hydrogen atom and then by an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or a derivative thereof on a compound represented by the formula (I) wherein R represents a hydrogen atom.
The esterification can be performed under the conditions described above for the esterification of the product of general formula (VI) by means of an acid of general formula (VII).
The replacement of the protecting groups G1 and G3 of the product of general formula (XXVII) by a hydrogen atom is carried out by treatment with zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60xc2x0 C. or by means of an inorganic or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, when G1 and G3 represent a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical. The replacement of the protecting group G3, when it represents a silylated radical or an acetal residue, can be carried out by treatment in acidic medium such as for example hydrochloric acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, propanol or isopropanol) or aqueous hydrofluoric acid at a temperature ranging from 0 to 40xc2x0 C., when it represents an acetal residue, the replacement of the Protecting group G1 then being carried out under the conditions described above. When G3 represents a group xe2x80x94CH2xe2x80x94Ph, the replacement of this protecting group with a hydrogen atom can be carried out by hydrogenolysis in the presence of a catalyst.
The acid of general formula (XXVI) can be obtained by saponification of an ester of general formula: 
in which Ar, R1, R5 and G3 are defined as above.
Generally, the saponification is carried out by means of an inorganic base (alkali metal hydroxide, carbonate or bicarbonate) in aqueous-alcoholic medium (methanol-water) at a temperature ranging from 10 to 40xc2x0 C.
The ester of general formula (XXVIII) can be obtained according to the usual methods for the preparation of ethers, and more particularly according to the procedures described by J -N. DENIS et al., J. Org. Chem., 51 46-50 (1986), from a product of general formula (XI).
Compounds of the formula (I) 
in which R represents an alkoxyacetyl radical, R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94CO in which R2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, may be made by a process comprising esterifying a compound of the formula (XXIX): 
in which G1 represents an alkoxyacetyl radical or other hydroxy-protecting group and Ra represents a radical Oxe2x80x94SO2xe2x80x94CF3 or forms, together with the carbon atom of the xcex1 methyl group, a cyclopropyl ring, with a lactam of the formula (XXX): 
wherein G3 is a hydroxy-protecting group chosen from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (xcex2-trimethylsilyloxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl, 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radicals, or CH2xe2x80x94Ph radicals in which Ph represents a phenyl radical optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms, and Ar and R1 are defined as above, optionally transforming the Oxe2x80x94SO2xe2x80x94CF3 radical into a cyclopropyl ring; and replacing G3 by a hydrogen atom and optionally G1 by a hydrogen atom, said method comprising the further step, if G1 is replaced by a hydrogen atom, of converting said G1 hydrogen atom to an alkoxyacetyl radical by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G1 by said hydrogen atom.
Compounds of the formula (I): 
wherein R represents butoxyacetyl, ethoxyacetyl, and isopropoxyacetyl, R1 represents a t-butoxycarbonyl radical, and Ar represents phenyl, may be made by the process comprising esterifying with an alkoxyacetic acid or derivative thereof, a compound of the formula (II): 
wherein G1 represents a hydrogen atom, and R3 and R4, which are identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R3 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R4 represents a hydrogen atom, or alternatively R3 and R4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, and opening the oxazaldine ring portoin of the compound of formula (II) to obtain the compound of formula (I).
Compounds of the formula (I): 
in which R represents an alkoxyacetyl radical, R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94CO in which R2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, may be made by a process comprising esterifying a compound of the formula (XXIX): 
in which G1 represents an alkoxyacetyl radical or other hydroxy-protecting group and Ra represents a radical Oxe2x80x94SO2xe2x80x94CF3 or forms, together with the carbon atom of the xcex1 methyl group, a cyclopropyl ring, with a free acid of the formula (VII): 
in which R3 and R4, which are identical or different represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R3 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R4 represents a hydrogen atom, or alternatively R3 and R4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring; and Ar and R1 are defined as above, optionally transforming the Oxe2x80x94SO2xe2x80x94CF3 radical into a cyclopropyl ring, and removing, if G1 is said other hydroxy-protecting group, said hydroxy-protecting group to obtain a hydrogen atom and converting said hydrogen atom to an alkoxyacetyl radical by action of an alkoxyacetic acid or derivative thereof on said compound obtained after replacement of said G1 hydroxy-protecting group by a hydrogen atom.
The new products of general formula (I) obtained using the procedures according to the invention can be purified according to known methods such as crystallization or chromatography.
The products of general formula (I) have remarkable biological properties.
In vitro, measurement of the biological activity is carried out on tubulin extracted from pig brain by the method of M. L. Shelanski et al., Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). The study of the depolymerization of the microtubules into tubulin is carried out according to the method of G. Chauvixc3xa9re et al., C. R. Acad. Sci., 293, sxc3xa9rie II, 501-503 (1981). In this study, the products of general formula (I) proved at least as active as taxol and Taxotere.
In vivo, the products of general formula (I) proved active in mice grafted with the B16 melanoma at doses ranging from 1 to 10 mg/kg intraperitoneally, as well as on other liquid or solid tumours.
The new compounds have anti-tumor properties, more particularly, activity against tumors which are resistant to Taxol(copyright) and Taxotere(copyright). Such tumors include, for example, colon tumors which have an elevated expression of mdr 1 gene (multi-drug resistant gene). Multi-drug resistance is the usual term relating to the resistance by a tumor against various compounds having differing structures and mechanisms of action. Taxoids are generally known to be highly recognized by experimental tumors such as P388/DOX, a P388 murine leukemia cell line selected for doxorubicin (DOC) resistance, which express mdr 1. The new compounds according to the present invention are less recognized by P388/DOX. More particularly, the new compounds are less recognized than Taxotere(copyright) by mdr 1.
In particular, it has been found that the new compounds of the present invention including the compounds of example 1, example 2 and example 3 have better multi-drug resistance properties than Taxol(copyright) and Taxotere(copyright). Additionally, it has surprisingly been found that the compound of example 3 has substantially better multi-drug resistance properties than the compounds of example 1 and example 2.